Alpha-Helices are central biological recognition elements, interacting with proteins, DNA and RNA. The ability to mimic this secondary structure element predictably with a small molecule would allow control of myriad biological events. However, despite the ubiquity of alpha-helical recognition, few examples exist of small molecule mimics of a-helices. The primary theme of this work is the development of small molecule mimics of Alpha-helices and their application to biological systems. In the process, we will examine the biological mechanisms of target recognition alpha-helices. Initial work will focus on mimicry of short recognition helices, proceeding to mimicry of extended alpha-helices. The acidic activation domains of the p53, p65 and VPI 6 proteins have been shown to interact with their target proteins through a short recognition helix, in which the primary interactions occur via hydrophobic residues at positions i, i+3 and i+4 (termed the FXXphiphi motif). We will prepare decalin-based scaffolds which allow presentation of the i, i+1, i+3 and i+4 residues (one face) of an alpha-helix. The scaffolds will be elaborated with the appropriate sidechains from the activation domain sequences. These molecules will be tested for binding to target proteins to assess scaffold suitability and effectiveness and for interaction specificity. Competition experiments with activation domain-derived peptides will determine that the same binding site is utilized. Mimics will be attached to DNA-binding domains to determine effectiveness in transcription activation. Additionally, the molecules will be attached to known small molecule DNA-binding motifs to generate cell-diffusible small molecule regulators of transcription.